Research ArticleCancer

The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer

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Sci. Signal.  17 Jan 2017:
Vol. 10, Issue 462, eaag0528
DOI: 10.1126/scisignal.aag0528

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Prometastatic roles for neuropilin 2b

Neuropilins are pleiotropic co-receptors for semaphorins and other growth factors, such as TGFβ. In established tumors, TGFβ promotes cell migration and metastasis. Using cell lines, mouse models, and primary patient material, Gemmill et al. found that the roles of the two neuropilin 2 isoforms were distinct in non–small cell lung cancer (NSCLC) cells. Experiments with cultured cells and xenografted tumors with high and low abundance of NRP2a and NRP2b showed that, in contrast to NRP2a, NRP2b inhibited primary tumor growth but mediated TGFβ-induced epithelial-to-mesenchymal transition, cell migration, metastasis, and drug resistance. High amounts of NRP2b in tumors correlated with that of the immunosuppressive ligand PD-L1 and with drug resistance, metastatic disease, and poor prognosis in patients. Selectively targeting this isoform may prevent disease progression and improve drug efficacy in some patients.

Abstract

Neuropilins (NRP1 and NRP2) are co-receptors for heparin-binding growth factors and class 3 semaphorins. Different isoforms of NRP1 and NRP2 are produced by alternative splicing. We found that in non–small cell lung cancer (NSCLC) cell lines, transforming growth factor–β (TGFβ) signaling preferentially increased the abundance of NRP2b. NRP2b and NRP2a differ only in their carboxyl-terminal regions. Although the presence of NRP2b inhibited cultured cell proliferation and primary tumor growth, NRP2b enhanced cellular migration, invasion into Matrigel, and tumorsphere formation in cultured cells in response to TGFβ signaling and promoted metastasis in xenograft mouse models. These effects of overexpressed NRP2b contrast with the effects of overexpressed NRP2a. Hepatocyte growth factor (HGF)–induced phosphorylation of the kinase AKT was specifically promoted by NRP2b, whereas inhibiting the HGF receptor MET attenuated NRP2b-dependent cell migration. Unlike NRP2a, NRP2b did not bind the PDZ domain scaffolding protein GAIP carboxyl terminus–interacting protein (GIPC1) and only weakly recruited phosphatase and tensin homolog (PTEN), potentially explaining the difference between NRP2b-mediated and NRP2a-mediated effects. Analysis of NSCLC patient tumors showed that NRP2b abundance correlated with that of the immune cell checkpoint receptor ligand PD-L1 as well as with epithelial-to-mesenchymal transition (EMT) phenotypes in the tumors, acquired resistance to epidermal growth factor receptor (EGFR) inhibitors, disease progression, and poor survival in patients. NRP2b knockdown attenuated the acquisition of resistance to the EGFR inhibitor gefitinib in cultured NSCLC cells. Thus, in NSCLC, NRP2b contributed to the oncogenic response to TGFβ and correlated with tumor progression in patients.

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